The current therapy for control of elevated intraocular pressure (IOP) or ocular hypertension which is believed to be a factor in the onset and progress of glaucoma is typically effected with a variety of topically applied agents which fall within four categories: .beta.-blockers, sympathomimetic agents, parasympatho-mimetic agents and cholinesterase inhibitors. The adjuvant oral administration of a carbonic anhydrase inhibitor (CAI) is practised when the above-described topical agent's side effects limits its use and/or it fails to achieve adequate IOP control. The orally active CAI's can exhibit serious side-effects such as anorexia, gastrointestinal upset and parasthesias. Therefore an intense and ongoing search has been mounted for a topically active CAI that would not exhibit such side effects due to the route of administration and inherent target organ specificity. This search has resulted in the discovery of a class of compounds by Baldwin et al (U.S. Pat. No. 4,797,413) of general formula: ##STR1## wherein R and R.sub.1 are lower alkyl, especially dorzolamide, wherein R is ethyl and R.sub.1 is methyl.
U.S. Pat. No. 4,797,413 discloses a process for preparing the racemic modification of the alkyl 3-(thien-2-ylthio)butyrate and its homologs. The prior art process comprises addition of the 2-thienyl-thiol (II) across the double bond of a substituted acrylic acid (IV) to yield the acid I: ##STR2## followed by synthesis of the final diastereomeric product, the isomers of which must be separated and each resolved to obtain the most active (S,S)-enantiomer. The isomer separations result in an automatic loss of the bulk of the chemical product.
U.S. Pat. No. 4,968,815 discloses a process for preparing the acid of structural formula I: ##STR3## which comprises treating a nucleophile of structure II with a compound of structure III as shown: ##STR4## wherein the R groups are as hereinafter defined. U.S. Pat. No. 4,968,814 and Blacklock et al., J. Org. Chem., 1993, 58, 1672-1679 also teaches a process for preparing the chiral intermediate formula I. However, these prior an processes involve many steps, are expensive and very time consuming.
It is therefore an object of this invention to provide a process for the synthesis of acid (I) for the synthesis of a chiral final product (V), dorzolamide, more economically than previously possible.